Alzheimer's disease, the most frequent cause of dementia and a major cause of morbidity and mortality in the elderly, is defined by histopathological features, notably neurofibrillary tangles and senile plaques. Because no animal model exists for the disorder, advances in understanding the pathogenesis of Alzheimer's disease have depended on studies of biopsy or postmortem human brain tissue. Previous studies have shown that disruption of the neuronal cytoskeleton, which normally functions to maintain cytoplasmic compartmentalization, intracellular transport and neuronal morphology, is a key feature of Alzheimer's disease. Paired helical filaments, the primary ultrastructural constituent of neurofibrillary tangles, contain the microtubule associated protein, tau as an integral component. Tau and other cytoskeletal proteins are reorganized in Alzheimer's disease, thereby providing a potential substrate for widespread degeneration and growth response. Our hypothesis is that degeneration and regeneration are critically dependent on cytoskeletal composition. A major goal of the present study is to establish the precise morphology and distribution of MAP2, type II Ca2+/calmodulin kinase and calbindin D28K immunoreactive neurons in the medial temporal lobe and their relationship to neurofibrillary tangles, as defined by thioflavine S, Hicks-Gallyas and tau staining, in aged controls and Alzheimer's disease patients. The medial temporal lobe encompasses a range of cortical and subcortical regions fundamental to memory processing which are lesioned in Alzheimer's disease. We will determine the sequence of neurofibrillary change by examining the interrelationship of tubulin, tau, ubiquitin, and MAP2 in degenerating neurons. Differentially affected regions will be examined in patients with Alzheimer's disease of variable severity, duration, and age of onset to determine the chronology of alterations. The nature and extent of growth response in Alzheimer's disease will be examined using markers associated with growth cones, including actin, GAP 43, and neural cell adhesion molecule (NCAM). The expression of tau protein in regenerating structures will be studied with hybridization histochemistry to determine if there is increased synthesis of tau in regenerating elements in Alzheimer's disease. These goals will be achieved using immunocytochemical, section Golgi, and local tract tracing methods at the light and electron microscopic levels. Specific procedures include immunoperoxidase, immunofluorescence, and immunogold procedures using well characterized antisera. Colocalization studies to determine the interrelationship of cytoskeletal proteins will be performed using double immunofluorescence and immunoperoxidase procedures.